Platelets are synthesized by the megakaryocytes, which develop from haematopoietic stem cells in a process of endomitosis. Protein synthesis in human platelets is slow, entirely depending on splicing of immature mRNA in this a-nucleate cell. Therefore, the synthesis of mechanisms that activate and suppress platelets functions is best studied in the maturing megakaryocyte. Fundamental differences in signaling pathways exist between stem cells and mature megakaryocytes. A striking example is the role of cAMP, being an activator of Ca2+ signaling in stem cells and a potent inhibitor in mature megakaryocytes and platelets. An important anti-thrombotic agent is clopidogrel which raises the cAMP level and suppresses platelet functions. Success of this drug depends on full down-regulation of the activating properties of cAMP observed in the stem cells during differentiation to mature megakaryocytes and platelet shedding. In about 15% of normal individuals down-regulation is incomplete, which may be a cause of clopidogrel resistance seen in large clinical trials.
The suppression of signaling pathways in platelets by insulin is also seen in mature megakaryocytes where insulin reduces the thrombin-induced rise in Ca2+. A cause of insulin-resistance of platelets from diabetics might be obesitas. Current studies are focused on the role certain adipokines, which interfere with this process through a rapid/reversible and persistent / irreversible mechanism introducing different types of insulin resistance and linking obesitas with platelet hyperactivity and possible CVD risk.
General Aim
To clarify abnormalities in platelet functions caused by abnormalities in the biogenesis of future platelet components.
On this project are working:
Drs. J. Gerrits, Ph.D. student